Platelets play a pivotal role in physiological hemostasis. However, in coronary arteries damaged by atherosclerosis, enhanced platelet aggregation, with subsequent thrombus formation, is a precipitating factor in acute ischemic events. Hence, pharmacological agents with antiplatelet actions are considered to be fundamental therapies in the prevention of atherothrombotic events.
Platelets normally circulate in a resting state and upon vascular injury they interact with components of the sub-endothelial matrix, particularly collagen and von Willebrand factor (vWF), via their respective receptors glycoprotein (GP) VI and GPIbN/IX. Agonists, such as collagen, ADP, arachidonic acid, epinephrine, thromboxane A2 (arachidonic acid-derived), and thrombin, are then released or produced to further amplify platelet activation by interacting with their respective membrane receptors. Hence, more circulating platelets from the blood flow are recruited to sustain hemostatic plug growth. The final pathway for all agonists is the activation of the platelet membrane GPIIb/IIIa integrin, leading to thrombus formation through fibrinogen bridges.
The most common antiplatelet agents currently used in clinical practice for the prevention of atherothrombosis are aspirin and clopidogrel. Their mechanisms of action are focused on inhibiting irreversibly amplification mechanisms of platelet activation by blocking the interaction of an agonist with its specific cell surface receptor. For instance, aspirin, as an irreversible inhibitor of cyclooxygenase (COX)-1, prevents arachidonic acid from being metabolized to prostaglandins G2/H2 and subsequently inhibits thromboxane A2 formation. Similarly, clopidogrel directly interferes with ADP binding to its P2Y12 receptor. However, antiplatelet agents, such as aspirin, are often associated with an increased risk of bleeding and frequently require gastric protection medications.